1. Field of the Invention
The invention relates to a novel anti-VEGF antibody, methods of using the antibody, in particular methods for treatment of conditions and diseases associated with VEGF-expression, such as cancer.
2. Background Information
It is well established that vascular endothelial growth factor (VEGF) and its receptors are key regulators of new blood vessel formation, or angiogenesis. The VEGF gene family has several members, including VEGF-A (also referred to herein as “VEGF”), VEGF-B, VEGF-C, VEGF-D, VEGF-E, and P1GF. See, Ho and Kuo, Int. J. Biochem Cell Biol. 2007; 39 (7-8): 1349-1357. There are numerous alternatively spliced isoforms of human VEGF, including VEGF165, VEGF121, VEGF189, and VEGF206. See, Ho and Kuo, Int. J. Biochem Cell Biol. 2007; 39 (7-8): 1349-1357; Ferrara et al., Nature Med. 2003; 9 (6):669-676. The VEGF165 isoform is the most prevalent and mitogenic and is most similar in properties to the 45 kDa native VEGF. See, Ho and Kuo, Int. J. Biochem Cell Biol. 2007; 39 (7-8): 1349-1357; Ferrara et al., Nature Med. 2003; 9 (6):669-676.
VEGF exists a 45 kD homodimeric glycoprotein which binds to two related tyrosine kinase receptors. Ferrara et al., Nature Med. 2003; 9 (6):669-676. VEGFR-1 (also known as Flt-1), is a high affinity receptor for VEGF whose function is not fully understood. VEGFR-2 (also known as KDR or Flk1), is the other high affinity receptor for VEGF, and is the receptor through which the pro-angiogeneic activity of VEGF is believed to occur. See Ferrara et al., Nature Med. 2003; 9 (6):669-676. VEGFR2 forms a dimer and autophosphorylates when bound to VEGF. Dougher and Terman, Oncogene. 1999; 18: 1619-1627. This, in turn, activates several signaling cascades that promote endothelial cell growth and migration, and which ultimately lead to angiogenesis. See Hicklin and Ellis, J. Clin. Oncol. 2005; 23 (5): 1011-1027.
During embryonic and postnatal development, VEGF participates in angiogenesis, vasculogenesis, and lymphangiogenesis. VEGF has also been found to play a role in adult processes, as well, including ovarian angiogenesis, endochondral bone formation, tissue regeneration, survival of hematopoietic stem cells, and regulation of erythropoietin. See, Ho and Kuo, Int. J. Biochem Cell Biol. 2007; 39 (7-8): 1349-1357. It is the involvement of VEGF in disease processes such as cancer and other neoplastic conditions, inflammatory disease, ocular disease, and ischemic disease that makes it a target for treatment.
Angiogenesis is a requirement for a tumor to grow beyond 1 to 2 mm. The formation of new vasculature is a result of the tumor environment “switching” on several pathways that promote tumor angiogenesis. Inhibition of VEGF-induced angiogenesis by a monoclonal antibody that specifically binds to VEGF was shown to suppress tumor growth in vivo. See Kim et al., Nature 1993; 362: 841-844, which ultimately led to the development of therapeutic antibody, bevacizumab. However, bevacizumab is a humanized version of a mouse antibody. Humanized antibodies have an increased risk of immunogenicity when introduced into the human body because they retain significant portions of a mouse protein that is recognized as foreign. Also, humanization of an antibody can lead to decreased affinity for the target protein, rendering it less effective. Accordingly, there exists a need for an anti-VEGF antibody that is generated from human sequence's and which has improved affinity for the VEGF protein.